Etor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ETORA

Composition:

Active substance: etoricoxib;

1 tablet contains 60 mg, 90 mg, or 120 mg of etoricoxib;

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, sodium croscarmellose, magnesium stearate;

Coating for 60 mg and 120 mg tablets: polyvinyl alcohol (E 1203), titanium dioxide (E 171), glycerol monostearate (E 471), indigo carmine aluminium lake (E 132), yellow iron oxide (E 172), talc, sodium lauryl sulfate, purified water;

Coating for 90 mg tablets: polyvinyl alcohol (E 1203), titanium dioxide (E 171), glycerol monostearate (E 471), talc, sodium lauryl sulfate, purified water.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

60 mg tablets: biconvex, oval-shaped tablets, film-coated, dark green in colour, engraved with "60" on one side and plain on the other.

90 mg tablets: biconvex, oval-shaped tablets, film-coated, white in colour, engraved with "90" on one side and plain on the other.

120 mg tablets: biconvex, oval-shaped tablets, film-coated, pale green in colour, engraved with "120" on one side and plain on the other.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Coxibs. ATC code M01A H05.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Etoricoxib is an oral selective inhibitor of cyclooxygenase-2 (COX-2) within the clinical dose range.

In clinical pharmacological studies, the medicinal product Etora dose-dependently inhibited COX-2 without inhibiting cyclooxygenase-1 (COX-1) when administered at doses up to 150 mg per day. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function.

Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms have been identified – COX-1 and COX-2. COX-2 is the inducible isoform of the enzyme triggered by inflammatory stimuli and is considered the primary factor responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation, and closure of the ductus arteriosus, as well as in the regulation of kidney and central nervous system functions (fever induction, pain perception, cognitive function). It may also participate in the process of ulcer healing. COX-2 has been identified in tissue surrounding gastric ulcers in humans, but its significance for ulcer healing has not been established.

Efficacy

In patients with osteoarthritis, etoricoxib at a dose of 60 mg once daily significantly improved pain symptoms and patient assessment of disease status. These positive effects were observed as early as on day 2 of treatment and persisted throughout the treatment period up to 52 weeks. In studies using etoricoxib at a dose of 30 mg once daily, the efficacy of this drug exceeded that of placebo over a 12-week treatment period (using outcome measures applied in other studies). In a dose-finding study, etoricoxib at a dose of 60 mg demonstrated significantly greater improvement compared to 30 mg with respect to all three primary endpoints after 6 weeks of treatment. The 30 mg dose has not been studied in hand osteoarthritis.

In patients with rheumatoid arthritis, etoricoxib at doses of 60 mg and 90 mg once daily significantly improved pain intensity, inflammation, and joint mobility. In studies evaluating the 60 mg and 90 mg doses, positive effects were maintained throughout the 12-week treatment period. In a study comparing the 60 mg and 90 mg doses, both etoricoxib regimens – 60 mg once daily and 90 mg once daily – were more effective than placebo. The 90 mg dose was superior to the 60 mg dose according to the Patient's Global Assessment of Pain (0–100 mm visual analog scale), with a mean improvement of -2.71 mm (95% CI: -4.98 mm, -0.45 mm).

In patients experiencing acute gouty arthritis attacks, etoricoxib at a dose of 120 mg once daily for 8 days reduced moderate to severe joint pain and inflammation compared to indomethacin at a dose of 50 mg three times daily. Reduction in pain intensity was observed as early as 4 hours after initiation of treatment.

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provided significant improvement in spinal pain, inflammation, and mobility limitations, as well as improved functional capacity. Clinical benefits of etoricoxib were observed on day 2 after initiation of therapy and persisted throughout the 52-week treatment period. In a second study evaluating the 60 mg versus 90 mg dose, etoricoxib at doses of 60 mg once daily and 90 mg once daily demonstrated similar efficacy compared to naproxen 1000 mg daily. In patients who did not show an adequate response to the 60 mg daily dose over 6 weeks, increasing the dose to 90 mg daily improved the assessment of spinal pain intensity (0–100 mm visual analog scale) compared to continuing 60 mg daily, with a mean improvement of -2.70 mm (95% CI: -4.88 mm, -0.52 mm).

In a clinical study of postoperative dental pain, etoricoxib 90 mg was administered once daily for up to three days. In the subgroup of patients with moderate baseline pain, etoricoxib 90 mg showed an analgesic effect similar to that of ibuprofen 600 mg (16.11 vs. 16.39; P=0.722) and superior to that of acetaminophen/codeine 600 mg/60 mg (11.00; P<0.001) and placebo (6.84; P<0.001), as measured by the proportion of patients achieving complete pain relief at 6 hours (TOPAR6). The proportion of patients reporting use of rescue analgesic medication within 24 hours was 40.8% in the etoricoxib 90 mg group, 25.5% in the ibuprofen 600 mg every 6 hours group, and 46.7% in the acetaminophen/codeine 600 mg/60 mg every 6 hours group, compared to 76.2% of patients receiving placebo. In this study, the onset of analgesic action (meaningful pain relief) with 90 mg etoricoxib was observed as early as 28 minutes after dosing.

Safety

Long-term Etoricoxib and Diclofenac Arthritis Trial (MEDAL) Program

The MEDAL program was a prospectively designed safety outcomes program evaluating cardiovascular safety based on pooled data from three randomized, double-blind, active comparator-controlled trials (the MEDAL, EDGE II, and EDGE studies).

In the MEDAL study, which was designed to assess cardiovascular effects, 17,804 patients with osteoarthritis and 5,700 with rheumatoid arthritis received etoricoxib 60 mg (osteoarthritis) or 90 mg (osteoarthritis and rheumatoid arthritis) or diclofenac 150 mg daily, with a mean treatment duration of 20.3 months (maximum 42.3 months, median 21.3 months). Only serious adverse reactions and discontinuations due to any adverse reactions were recorded in this study.

The EDGE and EDGE II studies compared gastrointestinal tolerability of etoricoxib and diclofenac. The EDGE study included 7,111 patients with osteoarthritis who received etoricoxib 90 mg daily (1.5 times higher than the recommended dose for osteoarthritis treatment) or diclofenac 150 mg daily, with a mean duration of 9.1 months (maximum 16.6 months, median 11.4 months). The EDGE II study included 4,086 patients with rheumatoid arthritis who received etoricoxib 90 mg daily or diclofenac 150 mg daily, with a mean duration of 19.2 months (maximum 33.1 months, median 24 months).

The combined MEDAL program included 34,701 patients with osteoarthritis and rheumatoid arthritis, treated for a mean duration of 17.9 months (maximum 42.3 months, median 16.3 months); approximately 12,800 patients were treated for more than 24 months. Patients enrolled in this program had varying baseline cardiovascular and gastrointestinal (GI) risk factors. Patients with recent myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention within 6 months prior to study enrollment were excluded. The use of gastroprotective agents and low-dose acetylsalicylic acid was permitted in the studies.

Overall safety

There were no significant differences in the frequency of thrombotic cardiovascular complications between etoricoxib and diclofenac. Cardiorenal adverse reactions were more frequently observed with etoricoxib than with diclofenac; this effect was dose-dependent (see detailed results below). Gastrointestinal and hepatic adverse reactions occurred significantly more frequently with diclofenac than with etoricoxib. The frequency of adverse reactions in the EDGE and EDGE II studies, as well as serious adverse reactions or those leading to drug discontinuation in the MEDAL study, was higher with etoricoxib than with diclofenac.

Cardiovascular safety

The incidence of confirmed thrombotic cardiovascular serious adverse reactions (including cardiac events, cerebrovascular events, and peripheral vascular events) was comparable between etoricoxib and diclofenac (data summarized in Table 1). There were no significant differences in the rates of thrombotic complications between etoricoxib and diclofenac across all analyzed subgroups, including patients with cardiovascular risk. When analyzed separately, the relative risk of confirmed serious thrombotic cardiovascular adverse reactions with etoricoxib 60 mg or 90 mg versus diclofenac 150 mg was similar.

Table 1

Incidence of confirmed thrombotic cardiovascular complications (combined MEDAL program)

Complications		Etoricoxib (N=16819) 25836 patient-years		Diclofenac (N=16483) 24766 patient-years		Comparison between treatment groups
		Incidence† (95% CI)		Incidence† (95% CI)		Relative risk (95% CI)
Confirmed serious cardiovascular thrombotic adverse events
Per protocol		1.24 (1.11; 1.38)		1.30 (1.17; 1.45)		0.95 (0.81; 1.11)
Intention-to-treat		1.25 (1.14; 1.36)		1.19 (1.08; 1.30)		1.05 (0.93; 1.19)
Confirmed cardiac complications
Per protocol		0.71 (0.61; 0.82)		0.78 (0.68; 0.90)		0.90 (0.74; 1.10)
Intention-to-treat		0.69 (0.61; 0.78)		0.70 (0.62; 0.79)		0.99 (0.84; 1.17)
Confirmed cerebrovascular complications
Per protocol	0.34 (0.28; 0.42)		0.32 (0.25; 0.40)		1.08 (0.80; 1.46)
Intention-to-treat	0.33 (0.28; 0.39)		0.29 (0.24; 0.35)		1.12 (0.87; 1.44)
Confirmed peripheral vascular complications
Per protocol	0.20 (0.15; 0.27)		0.22 (0.17; 0.29)		0.92 (0.63; 1.35)
Intention-to-treat	0.24 (0.20; 0.30)		0.23 (0.18; 0.28)		1.08 (0.81; 1.44)
†Events per 100 patient-years; CI – confidence interval. N – total number of patients in the per-protocol population. Per protocol: all complications during the study therapy or within 14 days after its discontinuation (except patients who took <75% of the study drug or used non-study nonsteroidal anti-inflammatory drugs (NSAIDs) for >10% of the total period). Intention-to-treat: all confirmed complications until the end of the study (including patients who may have received non-study interventions, followed by discontinuation of the study drug). Total number of randomized patients in the etoricoxib group – 17412, in the diclofenac group – 17289.

The cardiovascular mortality rate, as well as overall mortality, was similar in the etoricoxib and diclofenac treatment groups.

Cardiorenal complications

Approximately 50% of patients enrolled in the MEDAL study had a history of hypertension at baseline. In this study, the rate of treatment discontinuation due to adverse reactions related to hypertension was statistically significantly higher in the etoricoxib group than in the diclofenac group. The frequency of the adverse reaction "heart failure" (treatment discontinuation and serious events) was similar with etoricoxib 60 mg and diclofenac 150 mg, but the incidence of these reactions was higher with etoricoxib 90 mg compared to diclofenac 150 mg (statistically significant difference with etoricoxib 90 mg versus diclofenac 150 mg in the OA MEDAL subgroup). The frequency of confirmed adverse reactions related to congestive heart failure (events that were serious and required hospitalization or emergency care) was slightly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent. The rate of treatment discontinuation due to adverse reactions related to edema was significantly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent (statistically significant difference with etoricoxib 90 mg, but not with etoricoxib 60 mg).

Cardiorenal outcomes observed in the EDGE and EDGE II studies were consistent with those reported in the MEDAL study.

In individual studies of the MEDAL program, the absolute rate of treatment discontinuation in any etoricoxib treatment group (60 mg or 90 mg) was up to 2.6% for hypertension, up to 1.9% for edema, and up to 1.1% for congestive heart failure, with a higher rate of drug discontinuation observed with etoricoxib 90 mg compared to 60 mg.

Gastrointestinal tolerability results in the MEDAL program

A significantly lower rate of treatment discontinuation due to any gastrointestinal (GI) clinical complications (e.g., dyspepsia, abdominal pain, ulcers) was observed with etoricoxib compared to diclofenac in each of the three MEDAL program studies. The rates of treatment discontinuation due to GI clinical reactions per 100 patient-years over the entire study period were: 3.23 for etoricoxib and 4.96 for diclofenac in the MEDAL study; 9.12 for etoricoxib and 12.28 for diclofenac in the EDGE study; 3.71 for etoricoxib and 4.81 for diclofenac in the EDGE II study.

Gastrointestinal safety results from the MEDAL program

Upper gastrointestinal events were defined as perforations, ulcers, and bleeding. A subgroup of upper gastrointestinal events considered complicated included perforations, obstructions, and complicated bleeding; a subgroup of upper gastrointestinal events considered uncomplicated included uncomplicated bleeding and uncomplicated ulcers. A significantly lower rate of upper gastrointestinal events was observed with etoricoxib compared to diclofenac. There was no significant difference between etoricoxib and diclofenac in the rate of complicated events. For the subgroup of events such as upper gastrointestinal bleeding (combined complicated and uncomplicated), there was no significant difference between etoricoxib and diclofenac. The advantage of etoricoxib over diclofenac regarding upper gastrointestinal effects was not statistically significant in patients who were concurrently using low-dose acetylsalicylic acid (approximately 33% of patients).

The rate per 100 patient-years of confirmed complicated and uncomplicated clinical upper gastrointestinal events (perforations, ulcers, and bleeding) was 0.67 (95% CI 0.57; 0.77) with etoricoxib and 0.97 (95% CI 0.85; 1.10) with diclofenac, with a relative risk of 0.69 (95% CI 0.57; 0.83).

The rate of confirmed upper gastrointestinal events in elderly patients was assessed; the greatest reduction was observed in patients aged ≥75 years (1.35 [95% CI 0.94; 1.87] events per 100 patient-years with etoricoxib compared to 2.78 [95% CI 2.14; 3.56] with diclofenac).

Rates of confirmed clinical lower gastrointestinal events (perforation of the small or large intestine, obstruction, or bleeding) did not differ statistically between etoricoxib and diclofenac.

Hepatic safety results from the MEDAL program

Etoricoxib was associated with a statistically significantly lower rate of treatment discontinuation due to hepatic adverse reactions compared to diclofenac. In the combined MEDAL program, 0.3% of patients receiving etoricoxib and 2.7% of patients receiving diclofenac discontinued treatment due to hepatic adverse reactions. The rate per 100 patient-years was 0.22 with etoricoxib and 1.84 with diclofenac (p-value < 0.001 for etoricoxib compared to diclofenac). However, in the MEDAL program, most hepatic adverse reactions were non-serious.

Additional cardiovascular safety data regarding thrombotic complications

During clinical trials, excluding the MEDAL program studies, approximately 3100 patients received etoricoxib at doses ≥ 60 mg daily for 12 weeks or longer. There was no significant difference in the rates of confirmed serious thrombotic cardiovascular complications between patients receiving etoricoxib at doses ≥ 60 mg, placebo, or other NSAIDs (except naproxen). However, the frequency of such events was higher in patients receiving etoricoxib compared to those receiving naproxen 500 mg twice daily. The difference in antithrombotic activity between certain COX-1 inhibiting NSAIDs and selective COX-2 inhibitors may be clinically significant in patients at risk of thromboembolic complications. Selective COX-2 inhibitors reduce systemic (and thus possibly endothelial) prostacyclin formation without affecting platelet thromboxane. The clinical significance of these data is unknown.

Additional gastrointestinal safety data

During two 12-week double-blind endoscopic studies, the cumulative incidence of gastroduodenal ulcers was significantly lower in patients receiving etoricoxib 120 mg once daily compared to patients receiving naproxen 500 mg twice daily or ibuprofen 800 mg three times daily. The incidence of ulcers was higher with etoricoxib than with placebo.

Renal function study in elderly patients

A randomized, double-blind, placebo-controlled parallel-group study evaluated the effect of 15-day treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on urinary sodium excretion, blood pressure, and other renal function parameters in patients aged 60 to 85 years on a diet containing 200 mEq/day of salt. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion during 2-week treatment. All active comparator drugs showed an increase in systolic blood pressure compared to placebo, but etoricoxib was associated with a statistically significant increase on day 14 compared to celecoxib and naproxen (mean change in systolic blood pressure from baseline: etoricoxib 7.7 mm Hg, celecoxib 2.4 mm Hg, naproxen 3.6 mm Hg).

Pharmacokinetics.

Absorption

Etoricoxib is well absorbed after oral administration. Absolute bioavailability is approximately 100%. After administration of 120 mg once daily to steady state, the maximum plasma concentration (geometric mean Cmax = 3.6 µg/mL) is observed at approximately 1 hour (Tmax) after dosing in fasting adults. The geometric mean AUC0–24hr is 37.8 µg×hr/mL. Within the clinical dosing range, the pharmacokinetics of etoricoxib are linear.

Administration of 120 mg with food (high-fat meal) did not affect the extent of etoricoxib absorption. The rate of absorption was altered, characterized by a 36% decrease in Cmax and a 2-hour increase in Tmax. These findings are not considered clinically significant. In clinical studies, etoricoxib was administered regardless of food intake.

Distribution

Etoricoxib is approximately 92% bound to human plasma proteins over a concentration range of 0.05 to 5 µg/mL. The volume of distribution at steady state (Vdss) is approximately 120 L in humans.

Etoricoxib crosses the placental barrier in rats and rabbits and crosses the blood-brain barrier in rats.

Metabolism

Etoricoxib is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. The primary metabolic pathway is formation of the 6'-hydroxymethyl derivative catalyzed by cytochrome enzymes. CYP3A4 contributes to etoricoxib metabolism in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway, but their quantitative contributions have not been studied in vivo.

Five metabolites of etoricoxib have been identified in humans. The major metabolite is the 6'-carboxylic acid derivative of etoricoxib, formed by further oxidation of the 6'-hydroxymethyl derivative. These major metabolites are either inactive or weakly active COX-2 inhibitors. None of these metabolites inhibit COX-1.

Elimination

After a single intravenous dose of 25 mg radiolabeled etoricoxib to healthy volunteers, 70% of the radioactive dose was excreted in urine and 20% in feces, primarily as metabolites. Less than 2% was excreted unchanged.

Elimination of etoricoxib occurs almost entirely via metabolism followed by renal excretion. Steady-state concentrations of etoricoxib are reached within 7 days with 120 mg once daily, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 mL/min.

Special patient populations

Elderly patients. Pharmacokinetics in elderly patients (aged 65 years and older) are similar to those in younger patients.

Gender. Pharmacokinetics of etoricoxib are similar in males and females.

Hepatic impairment. In patients with mild hepatic impairment (5–6 points on the Child–Pugh scale), the mean AUC after administration of etoricoxib 60 mg once daily is approximately 16% higher than in healthy volunteers at the same dose. In patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale), the mean AUC after administration of etoricoxib 60 mg every other day is similar to that in healthy volunteers receiving 60 mg once daily; administration of etoricoxib 30 mg once daily has not been studied in this patient group. There are no clinical or pharmacokinetic data available for patients with severe hepatic impairment (≥10 points on the Child–Pugh scale).

Renal impairment. The pharmacokinetics of a single 120 mg dose of etoricoxib in patients with moderate and severe renal impairment, as well as in patients with end-stage renal disease undergoing hemodialysis, do not differ significantly from those in healthy volunteers. Etoricoxib is minimally removed during hemodialysis (dialysis clearance approximately 50 mL/min).

Pediatrics. The pharmacokinetics of etoricoxib in children (under 12 years of age) have not been studied.

In pharmacokinetic studies (n=16) conducted in adolescents (aged 12 to 17 years), pharmacokinetics in patients with body weight 40–60 kg receiving etoricoxib 60 mg once daily and in patients with body weight over 60 kg receiving etoricoxib 90 mg once daily were similar to those in adults receiving etoricoxib 90 mg once daily. The safety and efficacy of etoricoxib in pediatric patients have not been established.

Clinical characteristics.

Indications.

Symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as pain and inflammatory signs associated with acute gouty arthritis.

Short-term treatment of moderate postoperative pain associated with dental surgery.

The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of all individual patient risks.

Contraindications.

The medicinal product Etora is contraindicated:

• in cases of hypersensitivity to the active substance or any of the excipients of the medicinal product;
• in active peptic ulcer or active gastrointestinal bleeding;
• in patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria, or other allergic reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 inhibitors;
• during pregnancy and breastfeeding;
• in severe hepatic impairment (serum albumin < 25 g/L or ≥10 points on the Child-Pugh scale);
• when the calculated creatinine clearance is < 30 mL/min;
• in children under 16 years of age;
• in inflammatory bowel diseases;
• in congestive heart failure (NYHA II–IV);
• in patients with hypertension whose blood pressure values are persistently above 140/90 mm Hg and are insufficiently controlled;
• in diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Oral anticoagulants. In patients whose condition is stabilized by long-term warfarin therapy, administration of etoricoxib at a dose of 120 mg once daily is associated with an approximately 13% increase in the international normalized ratio (INR). Therefore, in patients receiving oral anticoagulants, INR values should be monitored frequently, especially during the first days of etoricoxib treatment or when its dosage is changed.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. NSAIDs may attenuate the effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonist with drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. The possibility of such interactions should be considered in patients receiving etoricoxib concomitantly with ACE inhibitors or angiotensin II receptor antagonists. Therefore, such combinations should be prescribed with caution, especially in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered at the start of combined therapy and periodically thereafter.

Acetylsalicylic acid. In a study involving healthy volunteers under steady-state conditions, administration of etoricoxib 120 mg once daily did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib may be administered concomitantly with acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose acetylsalicylic acid). However, concomitant use of low-dose acetylsalicylic acid and etoricoxib may increase the frequency of gastrointestinal ulceration and other complications compared to etoricoxib monotherapy. Concomitant use of etoricoxib with acetylsalicylic acid doses higher than prophylactic doses, as well as with other NSAIDs, is not recommended.

Cyclosporine and tacrolimus. Although interactions between etoricoxib and these drugs have not been studied, concomitant use of any NSAID with cyclosporine or tacrolimus may enhance the nephrotoxic effects of the latter. Renal function should be monitored when etoricoxib is used concomitantly with either of these drugs.

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other drugs

Lithium. NSAIDs reduce renal excretion of lithium, thereby increasing plasma lithium levels. Careful monitoring of plasma lithium levels and dose adjustment of lithium may be necessary during concomitant use of these drugs, as well as upon discontinuation of NSAID therapy.

MTX (methotrexate). Two studies evaluated the effects of etoricoxib administered at doses of 60 mg, 90 mg, or 120 mg once daily for 7 days in patients receiving weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 mg and 90 mg did not affect plasma concentrations or renal clearance of methotrexate. In one study, administration of etoricoxib 120 mg had no effect on methotrexate plasma concentration or renal clearance, whereas in another study, etoricoxib 120 mg increased methotrexate plasma concentration by 28% and decreased its renal clearance by 13%. Appropriate monitoring for signs of methotrexate toxicity should be performed when etoricoxib is co-administered with methotrexate.

Oral contraceptives. Etoricoxib 60 mg administered concomitantly with oral contraceptives containing 35 mcg ethinylestradiol and 0.5–1 mg norethindrone for 21 days increased the steady-state AUC_0–24hr of ethinylestradiol by 37%. Etoricoxib 120 mg administered concomitantly or 12 hours apart from the above-mentioned oral contraceptives increased the steady-state AUC_0–24hr of ethinylestradiol by 50–60%. This increase in ethinylestradiol concentration should be considered when selecting an oral contraceptive with different ethinylestradiol content to be used concomitantly with etoricoxib. Increased exposure to ethinylestradiol may increase the incidence of adverse reactions associated with oral contraceptives (e.g., venous thromboembolism in women at risk).

Hormone replacement therapy (HRT). Administration of 120 mg etoricoxib with hormone replacement therapy containing conjugated estrogens (0.625 mg of Premarin™) for 28 days increased the steady-state AUC_0–24hr of unconjugated estrone (by 41%), equilin (by 76%), and 17-β-estradiol (by 22%). The effect of etoricoxib doses recommended for long-term use (30 mg, 60 mg, and 90 mg) has not been studied. Compared to increasing the dose from 0.625 mg to 1.25 mg with Premarin™ monotherapy, the effect of etoricoxib 120 mg on exposure (AUC_0–24hr) of estrogenic components of Premarin™ was less than half. The clinical significance of this increase is unknown, and the use of high-dose Premarin™ concomitantly with etoricoxib has not been studied. This increase in estrogen concentration should be considered when selecting a hormonal preparation for postmenopausal use in combination with etoricoxib, as increased estrogen exposure raises the risk of adverse reactions during hormone replacement therapy.

Prednisone/prednisolone. In interaction studies, etoricoxib did not show clinically significant effects on the pharmacokinetics of prednisone/prednisolone.

Digoxin. Administration of etoricoxib 120 mg once daily for 10 days to healthy volunteers did not affect the steady-state AUC_0–24hr or renal excretion of digoxin. However, an increase in digoxin C_max (approximately 33%) was observed. This increase is generally not significant in most patients. Nevertheless, patients at high risk of digoxin toxicity should be monitored when etoricoxib and digoxin are co-administered.

Effect of etoricoxib on drugs metabolized by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and may also increase serum concentrations of ethinylestradiol. Since data on the impact of numerous sulfotransferases are still limited and the clinical effects of many drugs are under investigation, caution is advised when prescribing etoricoxib concomitantly with other drugs primarily metabolized by human sulfotransferases (e.g., oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolized by CYP isoenzymes

Based on in vitro data, inhibition of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 is not expected. In studies involving healthy volunteers, daily administration of etoricoxib 120 mg did not affect the activity of hepatic CYP3A4, as assessed by the erythromycin breath test.

Effect of other drugs on the pharmacokinetics of etoricoxib

The primary metabolic pathway of etoricoxib depends on CYP enzymes. CYP3A4 contributes to etoricoxib metabolism in vivo. In vitro studies suggest that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway of etoricoxib, although their quantitative contributions have not been studied in vivo.

Ketoconazole. Ketoconazole is a potent inhibitor of CYP3A4. When administered at 400 mg once daily for 11 days to healthy volunteers, ketoconazole did not have a clinically significant effect on the pharmacokinetics of a single 60 mg dose of etoricoxib (increase in AUC by 43%).

Voriconazole and miconazole. Concomitant administration of oral voriconazole or miconazole oral gel (both potent CYP3A4 inhibitors) with etoricoxib resulted in a slight increase in etoricoxib exposure, which, however, was not considered clinically significant according to published data.

Rifampicin. Concomitant administration of etoricoxib and rifampicin (a potent inducer of CYP enzymes) resulted in a 65% reduction in plasma concentrations of etoricoxib. This may be associated with recurrence of symptoms when used concomitantly with etoricoxib. While these data may suggest the need for dose adjustment, it is not recommended to use etoricoxib at doses exceeding those specified for each indication, as the combined use of rifampicin and etoricoxib at such doses has not been studied.

Antacids. Antacid medications do not have a clinically significant effect on the pharmacokinetics of etoricoxib.

Special precautions.

Gastrointestinal (GI) tract effects

Serious upper gastrointestinal complications (perforations, ulcers, or bleeding), sometimes fatal, have been reported in patients receiving etoricoxib.

NSAIDs should be prescribed with caution in patients at increased risk of gastrointestinal complications; elderly patients, patients taking any other NSAID or acetylsalicylic acid concomitantly, or patients with a history of gastrointestinal disorders, particularly peptic ulcers and gastrointestinal bleeding.

There is an increased risk of gastrointestinal adverse effects (gastrointestinal ulcer or other GI complications) with concomitant use of etoricoxib and acetylsalicylic acid (even at low doses). In long-term clinical trials, no significant difference in GI safety was observed between selective COX-2 inhibitors + acetylsalicylic acid and traditional NSAIDs + acetylsalicylic acid.

Cardiovascular effects

Clinical studies indicate that the use of drugs belonging to the class of selective COX-2 inhibitors may be associated with an increased risk of thrombotic complications (particularly myocardial infarction and stroke) compared to placebo and some NSAIDs. Since the risk of cardiovascular complications increases with higher doses and longer duration of etoricoxib treatment, the drug should be prescribed for the shortest possible duration and at the lowest effective daily dose. The need for symptomatic pain relief and response to treatment should be regularly reassessed, especially in patients with osteoarthritis.

Etoricoxib should be prescribed to patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful evaluation of the risk of complications.

Selective COX-2 inhibitors do not replace acetylsalicylic acid for the prevention of thromboembolic cardiovascular diseases, as they lack antiplatelet activity. Therefore, antiplatelet agents should not be discontinued.

Renal effects

Renal prostaglandins may play a compensatory role in maintaining renal perfusion. Therefore, in conditions associated with impaired renal perfusion, the use of etoricoxib may reduce prostaglandin synthesis and, consequently, renal blood flow, thereby worsening renal function. Patients with pre-existing severe renal impairment, uncompensated heart failure, or cirrhosis are at high risk of such reactions. Renal function should be monitored in these patients.

Fluid retention, edema, and arterial hypertension

As with other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and arterial hypertension have been observed in patients receiving etoricoxib. All NSAIDs, including etoricoxib, may cause development or exacerbation of congestive heart failure. Dose-dependent effects are described in the section "Pharmacological properties. Pharmacodynamics". The drug should be used with caution in patients with heart failure, left ventricular dysfunction, or a history of arterial hypertension, as well as in patients with edema due to any other cause. Appropriate measures, including discontinuation of etoricoxib, should be taken if clinical signs of worsening condition occur.

Etoricoxib, especially at high doses, may lead to more frequent and severe arterial hypertension compared to some other NSAIDs and selective COX-2 inhibitors. Therefore, arterial hypertension should be controlled before initiating etoricoxib therapy, and special attention should be paid to blood pressure monitoring during treatment. Blood pressure should be monitored within the first 2 weeks of treatment initiation and periodically thereafter. If blood pressure increases significantly, alternative therapy should be considered.

Hepatic effects

Elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately 3 times or more above the upper limit of normal (ULN)) were observed in approximately 1% of patients in clinical trials receiving etoricoxib at doses of 30 mg, 60 mg, and 90 mg daily for up to 1 year.

All patients with symptoms or laboratory signs of hepatic dysfunction should be monitored. Etoricoxib should be discontinued in case of signs of liver injury or persistent abnormal liver function tests (≥3 times ULN).

General precautions

If impairment of any organ system listed above occurs during treatment, appropriate measures should be taken and discontinuation of etoricoxib should be considered. Adequate medical monitoring is required when etoricoxib is administered to elderly patients and patients with renal, hepatic, or cardiac impairment.

Initiation of etoricoxib therapy should be done with caution in dehydrated patients. Rehydration is recommended prior to starting etoricoxib.

Serious skin reactions, in some cases fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported during post-marketing surveillance with NSAIDs and some selective COX-2 inhibitors (see section "Adverse reactions"). The highest risk of such reactions occurs early in therapy, and onset is usually within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been observed in patients taking etoricoxib. Some selective COX-2 inhibitors may increase the risk of skin reactions in patients with a history of allergic reactions to any drug. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or other signs of hypersensitivity.

Etoricoxib may mask signs of fever and other symptoms of inflammation.

Concomitant use of etoricoxib and warfarin or other oral anticoagulants should be done with caution.

The use of etoricoxib, as with other drugs that inhibit cyclooxygenase/prostaglandin synthesis, is not recommended in women attempting to conceive.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

There are no clinical data on the use of etoricoxib during pregnancy. Animal studies have shown reproductive toxicity. The potential risk to pregnant women is unknown. The use of etoricoxib during the third trimester of pregnancy, as with other drugs that inhibit prostaglandin synthesis, may result in uterine inertia and premature closure of the ductus arteriosus. Cases of impaired fetal renal function leading to reduced amniotic fluid volume (oligohydramnios) have been reported in pregnant women taking nonsteroidal anti-inflammatory drugs (NSAIDs) from the 20th week of gestation onward. In some cases, this may lead to renal impairment in newborns. These effects may occur soon after initiation of NSAID therapy; oligohydramnios is usually reversible upon discontinuation of treatment. Etoricoxib is contraindicated during pregnancy. If a woman becomes pregnant while taking etoricoxib, the drug should be discontinued immediately.

Breastfeeding

It is unknown whether etoricoxib passes into human breast milk. In rats, etoricoxib is excreted in milk. Women taking etoricoxib should not breastfeed.

Fertility

The use of etoricoxib, as with other COX-2 inhibitors, is not recommended in women attempting to conceive.

Ability to influence reaction speed when driving or operating machinery

Patients who experience dizziness, vertigo, or somnolence while taking etoricoxib should not drive or operate machinery.

Method of Administration and Dosage

The medicinal product Etorа is administered orally. The drug can be taken regardless of food intake. The onset of the drug's effect occurs faster when taken before meals. This should be taken into account when rapid symptom relief is required.

Since the risk of cardiovascular adverse events with etoricoxib increases with higher doses and longer duration of exposure, treatment should be initiated using the shortest possible duration and the lowest effective daily dose. The need for symptom relief and response to therapy should be periodically reassessed, especially in patients with osteoarthritis.

Osteoarthritis

The recommended dose is 30 mg once daily. In some patients, if symptoms are insufficiently relieved, increasing the dose to 60 mg once daily may improve efficacy. If no therapeutic improvement is observed, alternative treatment options should be considered.

Rheumatoid Arthritis

The recommended dose is 60 mg once daily. In some patients, if symptoms are insufficiently relieved, increasing the dose to 90 mg once daily may enhance the therapeutic effect. Once clinical stability is achieved, the dose should be reduced to 60 mg once daily. If no improvement is observed, alternative treatment options should be considered.

Ankylosing Spondylitis

The recommended dose is 60 mg once daily. In some patients, if symptoms are insufficiently relieved, increasing the dose to 90 mg once daily may improve the therapeutic effect. Once clinical stability is achieved, the dose should be reduced to 60 mg once daily. If no improvement is observed, alternative treatment options should be considered.

Acute Pain

In the event of acute pain, etoricoxib should be used only during the acute symptomatic period.

Acute Gouty Arthritis

The recommended dose is 120 mg once daily. In clinical trials of acute gouty arthritis, etoricoxib was administered for 8 days.

Postoperative Dental Pain

The recommended dose is 90 mg once daily for up to 3 days. Some patients may require additional postoperative analgesia.

Doses exceeding those recommended for each indication have not demonstrated additional efficacy or have not been studied. Therefore:

• The dose in osteoarthritis should not exceed 60 mg per day;
• The dose in rheumatoid arthritis and ankylosing spondylitis should not exceed 90 mg per day;
• The dose in acute gout should not exceed 120 mg per day for a maximum treatment duration of 8 days;
• The dose for acute pain following dental surgery should not exceed 90 mg per day for a maximum of 3 days.

Elderly Patients

Dose adjustment is not required for elderly patients. As with other drugs, etoricoxib should be prescribed with caution in elderly patients.

Hepatic Impairment

Regardless of the indication, patients with mild hepatic impairment (Child–Pugh score 5–6) should not exceed a dose of 60 mg once daily. Patients with moderate hepatic impairment (Child–Pugh score 7–9) should not exceed a dose of 30 mg once daily, regardless of the indication.

Clinical experience is limited, particularly in patients with moderate hepatic impairment; therefore, the drug should be used with caution. There is no clinical experience with etoricoxib in patients with severe hepatic impairment (Child–Pugh score ≥10); therefore, the drug is contraindicated in these patients.

Renal Impairment

Dose adjustment is not required in patients with creatinine clearance ≥30 mL/min. Etoricoxib is contraindicated in patients with creatinine clearance <30 mL/min.

Children

Etoricoxib is contraindicated in children under 16 years of age.

Overdose

During clinical trials, single doses of etoricoxib up to 500 mg or multiple doses up to 150 mg daily for 21 days did not result in significant toxic effects. Cases of acute etoricoxib overdose have been reported, although adverse reactions were not commonly reported. The most frequently observed adverse reactions were consistent with the safety profile of etoricoxib (such as gastrointestinal, cardiac, and renal events).

In the event of overdose, standard supportive measures should be implemented, such as removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring, and supportive treatment as needed.

Etoricoxib is not eliminated by hemodialysis; it is unknown whether the drug is eliminated by peritoneal dialysis.

Adverse reactions

The safety of etoricoxib was evaluated in clinical studies involving 9,295 patients, including 6,757 patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis (approximately 600 patients with osteoarthritis or rheumatoid arthritis received treatment for 1 year or longer).

During clinical studies, the adverse event profile was consistent in patients with osteoarthritis or rheumatoid arthritis who received etoricoxib for 1 year or longer.

In a clinical study involving patients with acute gouty arthritis, etoricoxib was administered at a dose of 120 mg once daily for 8 days. The adverse event profile in this study was generally similar to that observed in studies involving patients with osteoarthritis, rheumatoid arthritis, and chronic low back pain.

In the cardiovascular safety assessment program, data from three active-controlled studies showed that 17,412 patients with osteoarthritis or rheumatoid arthritis received etoricoxib (at doses of 60 mg or 90 mg) for a mean duration of approximately 18 months. Safety data and more detailed information on this program are provided in the section "Pharmacological properties".

During clinical studies involving patients with acute postoperative pain following dental, abdominal-gynecological surgical procedures, including 1,222 patients who received etoricoxib (at doses of 90 mg or 120 mg), the adverse event profile was generally similar to that observed in studies involving patients with osteoarthritis, rheumatoid arthritis, and chronic low back pain.

The adverse reactions listed below were reported more frequently with the use of the drug than with placebo during clinical studies in patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis who received etoricoxib at doses of 30 mg, 60 mg, or 90 mg for 12 weeks (MEDAL program studies, short-term acute pain studies, and post-marketing experience).

Table 2

System organ class	Adverse reactions	Frequency category*
Infections and infestations	alveolar osteitis	common
	gastroenteritis, upper respiratory tract infections, urinary tract infections	uncommon
Blood and lymphatic system disorders	anemia (mainly due to gastrointestinal bleeding), leukopenia, thrombocytopenia	uncommon
Immune system disorders	hypersensitivity‡ ß	uncommon
	angioneurotic edema, anaphylactic/anaphylactoid reactions, including shock‡	rare
Metabolism and nutrition disorders	edema/fluid retention	common
	decreased or increased appetite, weight gain	uncommon
Psychiatric disorders	anxiety, depression, impaired cognition, hallucinations‡	uncommon
	confusion‡, restlessness‡	rare
Nervous system disorders	dizziness, headache	common
	dysgeusia, insomnia, paresthesia/hypoesthesia, somnolence	uncommon
	intracranial hemorrhage	frequency unknown
Eye disorders	blurred vision, conjunctivitis	uncommon
Ear and labyrinth disorders	tinnitus, dizziness	uncommon
Cardiac disorders	palpitations, arrhythmia‡	common
	atrial fibrillation, tachycardia‡, congestive heart failure, non-specific ECG changes, angina pectoris‡, myocardial infarction§	uncommon
Vascular disorders	hypertension	common
	flushing, cerebrovascular disorder§, transient ischemic attack, hypertensive crisis‡, vasculitis‡	uncommon
	deep vein thrombosis	frequency unknown
Respiratory, thoracic and mediastinal disorders	bronchospasm‡	common
	cough, dyspnea, epistaxis	uncommon
	pulmonary embolism	frequency unknown
Gastrointestinal disorders	abdominal pain	very common
	constipation, flatulence, gastritis, heartburn/acid reflux, diarrhea, dyspepsia/epigastric discomfort, nausea, vomiting, esophagitis, oral ulcers	common
	abdominal distension, altered bowel habit, dry mouth, gastroduodenal ulcers, peptic ulcers including perforation and gastrointestinal hemorrhage, irritable bowel syndrome, pancreatitis‡	uncommon
Hepatobiliary disorders	elevated ALT, elevated AST	common
	hepatitis‡	rare
	hepatic failure‡, jaundice‡	rare†
Skin and subcutaneous tissue disorders	ecchymosis	common
	facial swelling, pruritus, rash, erythema‡, urticaria‡	uncommon
	Stevens-Johnson syndrome‡, toxic epidermal necrolysis‡, persistent drug eruption‡	rare†
Musculoskeletal and connective tissue disorders	muscle spasms/cramps, musculoskeletal pain/stiffness	uncommon
Renal and urinary disorders	proteinuria, increased serum creatinine, renal failure/dysfunction‡ (see section "Special warnings and precautions for use")	uncommon
General disorders and administration site conditions	asthenia/fatigue, influenza-like symptoms	common
	chest pain	uncommon
Investigations	increased blood urea nitrogen, increased creatine phosphokinase, hyperkalemia, increased uric acid	uncommon
	decreased blood sodium	rare

* The frequency category is defined for each adverse reaction term according to the frequency in the clinical trial database: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000).

‡ Adverse reaction identified during post-marketing surveillance. Frequency was determined based on the highest frequency observed in clinical trials (data collected for approved indications and doses).

† The frequency category "rare" was defined in accordance with the Guideline on summary of product characteristics (SmPC) (2nd revision, September 2009), based on the calculated upper limit of the 95% CI for 0 events, taking into account the number of participants who received Etorra in the phase III pooled analysis by dose and indication (n=15,470).

ß Hypersensitivity includes the following terms: allergy, drug allergy, drug hypersensitivity, hypersensitivity, unspecified hypersensitivity, hypersensitivity reaction, and unspecified allergy.

§ Based on analyses of long-term, placebo- and active-controlled clinical trials, selective COX-2 inhibitors have been associated with an increased risk of serious arterial thrombotic events, including myocardial infarction and stroke. Based on available data, it is unlikely that the absolute risk increase for such events exceeds 1% per year (uncommon).

Serious adverse reactions reported with NSAID use include nephrotoxicity, such as interstitial nephritis and nephrotic syndrome; therefore, the occurrence of these events cannot be excluded with etoricoxib use.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life.

4 years.

Storage conditions.

No special temperature requirements. Store in the original packaging to protect from moisture. Keep out of reach of children.

Packaging.

7 tablets in a blister pack. 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Rontis Hellas Medical and Pharmaceutical Products S.A.

Manufacturer's address and location of business operations.

Larissa Industrial Area, P.O. Box 3012, Larissa, 41 500, Greece